Secondary Logo

Journal Logo

Two-dose Epoetin Alfa Reduces Blood Transfusions Compared with Autologous Donation

Hardwick, Mary, E; Morris, Beverly, M; Colwell, Clifford, W, Jr

Clinical Orthopaedics and Related Research: June 2004 - Volume 423 - Issue - p 240-244
doi: 10.1097/01.blo.0000130206.58617.9e

This study evaluated whether patients receiving a two-dose regime of epoetin alfa received less allogeneic blood than patients donating autologous blood before primary hip arthroplasty. Consenting patients with a hemoglobin level between 12 and 15 g/dL were randomly assigned to a two-dose administration of epoetin alfa (19 patients) or autologous donation (21 patients). Sixteen percent of the patients in the epoetin alfa group and 52% of the patients in the autologous donation group received transfusions, with a mean volume of 90 cc per patient in the epoetin alfa group and 340 cc in the autologous donation group. Hemoglobin was similar at screening; however, the epoetin alfa group achieved a higher hemoglobin (14.6 g/dL) than the autologous donation group (12.6 g/dL) before surgery. Hemoglobin remained significantly higher in the epoetin alfa group for 3 days after surgery. Administration of two doses of epoetin alfa provided patients with effective and safe reduction of allogeneic blood transfusions and decreased the necessity and difficulty of autologous donation before total hip arthroplasty.

From the Scripps Clinic, La Jolla, CA.

Received: June 4, 2003

Revised: October 16, 2003; December 12, 2003

Accepted: February 18, 2004

OrthoBiotech, Inc, a subsidiary of Johnson & Johnson, funded this study. Each author certifies that he or she has no commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements) that might pose a conflict of interest in connection with the submitted article. Ms. Morris was employed by Scripps Clinic at the time this study was done, but has since changed employment and is currently employed by DePuy, a Johnson & Johnson Company, PO Box 988, 700 Orthopaedic Drive, Warsaw, IN 46581-0988.

Correspondence to: C. W. Colwell, MD, Scripps Clinic Center for Orthopaedic Research and Education, 11025 N. Torrey Pines Rd, Suite 140, La Jolla, CA 92037. Phone: 858-332-0125; Fax: 858-332-0136; E-mail:

Epoetin alfa is used to prevent anemia in major elective surgery, including total joint arthroplasty. Previous studies confirmed that a weekly dosing regimen of epoetin alfa based on weight for 2–4 weeks is effective,7,13 however, the current study defines a minimum effective fixed dose and duration of epoetin alfa in patients who are not donating autologous blood before surgery. No previous studies have reported the results of a two-dose regime by evaluating patients having elective total hip arthroplasty (THA).

The primary outcome investigated in four clinical studies was the incidence of allogeneic blood transfusion.1,3,5,6 Between 16% and 23% of the patients treated with epoetin alfa perioperatively received a blood transfusion. In contrast, the occurrence of transfusion ranged from 45–54% in patients treated with a placebo. Epoetin alfa was tolerated well and the prevalence of thrombotic or vascular events was similar between treatment groups and placebo groups.1,5,6 The purpose of the current study was to compare a two-dose regime of epoetin alfa (PROCRIT, Ortho Biotech, Inc, Raritan, NJ) with autologous donation before surgery for reduction of perioperative blood transfusions, particularly allogeneic blood transfusions, in patients having THA.

Back to Top | Article Outline


Patients between 18 and 85 years of age having elective primary THA were enrolled in this Human Subjects Committee approved, open-label, prospective, randomized, parallel-group study between September 1998 and May 2000. Patients included in the study had a hemoglobin level between 12 g/dL and 15 g/dL at the pretreatment evaluation. Exclusion criteria included patients with a history of clinically significant disease pertaining to neurologic, pulmonary, endocrine, gastrointestinal, genitourinary, or cardiovascular systems. Patients also were excluded for a known history of deep vein thrombosis or pulmonary embolism, gastrointestinal bleeding within 6 months before surgery, long-term anticoagulation therapy, presence of primary hematologic disease including iron or cofactor deficiency, drug or alcohol abuse, uncontrolled seizures, or chronic obstructive pulmonary disease.

Before surgery, patients were randomly assigned to one of two treatment groups: a two-dose administration of epoetin alfa or an autologous donation group. In the epoetin alfa group, patients received epoetin alfa 40,000 IU one time per week for 2 weeks, administered 14 days before surgery and 7 days before surgery. At the time of each injection, vital signs were recorded and hemoglobin levels were evaluated by a hemoglobin photometer (Hemocue, Inc, Mission Viejo, CA). If the hemoglobin level was greater than 15 g/dL, epoetin alfa was not administered.

Patients assigned to the autologous donation group donated one or two units of blood before surgery. The first donation occurred 3–4 weeks before surgery. The second unit, when required by the treating surgeon, occurred at least 72 hours before surgery. Beginning on the day of the first dose of epoetin alfa, or the first autologous donation, patients began 300 mg of an oral polysaccharide-iron complex (Niferex, Central Pharmaceuticals, Inc, Seymour, IN) three times daily and continued this regimen until the day before surgery. All patients received the same protocol for deep venous thrombosis prophylaxis, enoxaparin (Lovenox, Aventis Pharma, Collegeville, PA), 40 mg subcutaneously daily, beginning on the day of surgery and continuing through postoperative Day 7.

A complete blood count was done on the day of surgery, before and after surgery, and on Days 1, 2, and 3 after surgery. Other data collected included blood loss, blood transfusion, reason for blood transfusion, adverse events, length of hospital stay, and blood discarded in the autologous donation group. All patients received normotensive general anesthesia. Intraoperative blood salvage was available for all patients, but was not used if the drainage was less than 1000 cc.

Back to Top | Article Outline

Statistical Methods and Analysis

Primary efficacy variables were volume of blood transfused and volume of allogeneic blood transfused. Other efficacy variables assessed included the mean change in hemoglobin, serum iron level, serum iron saturation, and reticulocyte count. Alpha level was set at 0.05 with a power of 80 for this study. All efficacy variables were analyzed using descriptive statistics and the unpaired two-tailed Student’s t test. Microsoft Excel (Microsoft Corporation, Redmond, WA) was used for this analysis.

Back to Top | Article Outline


Forty-five patients were enrolled in the study with 40 (88%) patients completing study parameters. Four patients in the autologous donation group were excluded from the study before surgery. Of the four patients, one patient was unable to donate blood because of poor venous access, two patients cancelled surgery, and one patient was unable to donate blood because of a clerical error. One patient in the epoetin alfa group was withdrawn because of hemoglobin greater than 15 g/dL at the time of both doses. Of the 40 patients who completed the study, 19 (48%) were in the epoetin alfa group, and 21 (52%) were in the autologous donation group.

Patient characteristics, including age, gender, weight, anesthesia time, estimated blood loss, and length of stay were similar for both groups (Table 1). Blood loss during surgery was estimated by the surgeon, ranging from 200 cc to 1300 cc, with a mean blood loss of 576 cc (± 355 cc) in the epoetin alfa group and 545 cc (± 279 cc) in the autologous donation group.

Table 1

Table 1

Three patients (10%) in the epoetin alfa group received 1710 cc (4 U) of blood with two of the patients receiving 750 cc (2 U) allogeneic blood (Table 2). One patient in the epoetin alfa group received an allogeneic transfusion, one received allogeneic and salvaged blood, and one received salvaged blood. The two patients in the epoetin alfa group who received an allogeneic transfusion had a hemoglobin decrease of 0.04 g/dL from the first screening for hemoglobin to the hemoglobin screening done before surgery on the day of surgery. In the epoetin alfa group, six of 19 patients (32%) did not receive the second dose of epoetin alfa because their hemoglobin was greater than 15 g/dL after the first injection. The patient who received an allogeneic and a salvaged blood transfusion was morbidly obese, weighing 268 pounds. Epoetin alfa was safe and well tolerated in all patients.

Table 2

Table 2

Eleven patients (48%) in the autologous donation group received 7150 cc (17 U) of blood with three patients (14%) requiring transfusion of 1950 cc (5 U) of allogeneic blood (Table 2). Sixteen of 21 patients (76%) predonated one unit of blood and five patients (24%) predonated two units. A mean of 472 cc per patient was predonated. None of the patients in the autologous group received salvaged blood. Of the 26 autologous units predonated, 12 (46%) were discarded.

Although the percentage of patients receiving allogeneic blood was similar (11% in the epoetin alfa group and 14% in the autologous donation group), the autologous donation group used 62% more allogeneic blood than the epoetin alfa group. The mean volume of blood transfused was 90 cc (± 220 cc; 0.15 U) per patient in all 19 patients in the epoetin alpha group and 340 cc (± 466 cc; 0.16 U) per patient in all 21 patients in the autologous donation group (p = 0.04) (Fig 1). Patients receiving allogeneic blood received a mean volume of 375 cc (± 106 cc) in two patients in the epoetin alpha group and 650 cc (± 229 cc) in three patients in the autologous donation group (Fig 1).

Fig 1.

Fig 1.

The reasons for patients receiving transfusions in both groups included vertigo with activity (30%), decreased hemoglobin and hematocrit (25%), greater than 900 cc blood loss (20%), decreased urine output (15%), tachycardia (5%), and shortness of breath (5%). The mean pretransfusion hemoglobin of all patients receiving transfusions was 9.6 g/dL.

At screening, the mean hemoglobins were similar between the epoetin alfa group (13.7 g/dL) and the autologous donation group (13.8 g/dL). However, before surgery on the day of surgery, the epoetin alfa group mean hemoglobin was 14.6 g/dL (± 1.1 g/dL), 2 g/dL higher than the autologous donation group hemoglobin of 12.6 g/dL (± 1.2 g/dL) (p < 0.001). Although the hemoglobin dropped after surgery in both groups, the hemoglobin level was significantly higher (p < 0.007) through the third day after surgery in the patients treated with epoetin alfa (Fig 2), despite more patients receiving transfusions with a larger volume of blood in the autologous donation group.

Fig 2.

Fig 2.

Patients receiving transfusions had lower serum iron saturation and serum iron levels than patients not requiring transfusion before surgery on the day of surgery (Table 3). The reticulocyte counts, although lower in patients who received transfusions in the epoetin alfa and the autologous donation groups, were similar between groups and between patients who received transfusions and patients who did not receive transfusions. Reticulocyte count was highest (2.5%) in the patients who received epoetin alfa who did not need transfusions (Table 3).

Table 3

Table 3

Back to Top | Article Outline


Numerous options are available to the orthopaedic surgeon to prevent the complications of postoperative anemia and allogeneic transfusions, including technical issues of the surgery such as mini-incision, hemodilution,11 blood salvaging and reinfusion during and after surgery,4,8 hypotensive anesthesia,10 autologous donation, and epoetin alfa. Although all of these modalities have indications for use, hemoglobin management should begin before surgery in elective total joint arthroplasty. Epoetin alfa and autologous donation, therefore, offer a proactive approach to managing perioperative anemia.

Cost of various treatments for surgical anemia is a topic for discussion. In examining patient charges at our institution, a unit of autologous blood was $391, a unit of donor specific blood was $569, and a unit of allogeneic blood was $514. The pharmacy charged $489 for 40,000 U of epoetin alfa, making the total cost for the two doses $978. Therefore, a patient would have to receive two or more units of any type of blood to equal the cost of two doses of epoetin alfa.

Three major, double-blind, placebo-controlled studies involving 724 patients, with hemoglobin levels greater than 10 g/dL to 13 g/dL or less, having major elective orthopaedic surgery1,3,5 showed that treatment with 300 IU/kg epoetin alfa per day, for at least 14 days, beginning 10 days before surgery and continuing until the third or fourth day after surgery, decreased the number of patients requiring transfusion compared with patients given a placebo. Similar to this study, the benefits observed included increased hemoglobin before surgery and a smaller decrease in hemoglobin after surgery (Table 4).

Table 4

Table 4

A fourth study done by Goldberg6 in 1996 was the first randomized prospective clinical trial comparing a weekly dosing regimen, 600 IU/kg epoetin each week for 3 weeks and on the day of surgery, with a daily dosing regimen, 300 IU/kg epoetin daily for 10 days before surgery, on the day of surgery, and on Day 4 after surgery. Goldberg6 reported that daily dosing efficacy could be achieved by implementing weekly regimens with a lower total dose of epoetin. In these four clinical studies,1,3,5,6 between 16% and 23% of the patients treated with epoetin alfa perioperatively received a blood transfusion. In contrast, the occurrence of transfusion ranged from 45–54% in patients treated with a placebo.

In our study, patients with a hemoglobin between 12 g/dL and 15 g/dL receiving two weekly doses of epoetin alfa (40,000 IU) before surgery required fewer allogeneic blood transfusions and had a higher hemoglobin before and after surgery than patients donating autologous blood. Although the number of patients in this study seems small, the volume of blood transfused per patient reached significance (p = 0.04), as did the hemoglobin level difference (p < 0.007) at the time of surgery and for the 3 days after surgery despite the autologous group receiving a larger volume of blood. The sample size was adequate to detect a reduction of blood transfusion per patient of 300 cc or allogeneic blood transfusion per patient of 150 cc in the epoetin alfa group with a power of 80% or greater.

When to give a patient a transfusion has been controversial. For many years, the traditional rule was the 10/30 rule (10 g/dL hemoglobin/30% hematocrit).12 The 1988 National Institutes of Health consensus conference9 provided guidelines for transfusion targets, or triggers, lowering the hemoglobin level to 8 g/dL and directed attention toward assessment of clinical need and symptoms, rather than only hemoglobin and hematocrit values. Without a specific definition of transfusion triggers, the surgeon has to determine the trigger for each patient. Five factors influencing the decision to intervene when a patient is anemic were proposed by Carson2: (1) the risk of morbidity and mortality, (2) the patient’s age and comorbidity, (3) the anticipated operative blood loss, (4) the likelihood that operative treatment will reduce the risk of morbidity and mortality, and (5) the economic consequences of intervention. Observational transfusion triggers were examined in this study; however, the population was not large enough or sufficiently controlled to draw conclusions about ideal transfusion triggers.

The two-dose regimen of epoetin alfa offers the potential advantage of greater convenience for patients and physicians by requiring fewer injections and clinic visits for drug administration. It also eliminated the waste of discarding units of autologous blood and the logistics required by patients, physicians, nurses, and hospital blood banks to collect, prepare, and transfuse these donations. This prospective randomized clinical study confirmed the efficacy and safety of the two-dose epoetin alfa regimen, administered before THA, as a mechanism of reducing transfusion requirements by increasing hemoglobin levels before and after surgery in this specific subset of patients.

Back to Top | Article Outline


1. Canadian Orthopedic Perioperative Erythropoietin Study Group: Effectiveness of perioperative recombinant human erythropoietin in elective hip replacement. Lancet 341:1227–1232, 1993.
2. Carson JL: Morbidity risk assessment in the surgically anemic patient. Am J Surg 170(6A Suppl):32S–36S, 1995.
3. de Andrade JR, Frei D, Guilfoyle M: Integrated analysis of thrombotic/vascular event occurrence in epoetin alfa-treated patients undergoing major, elective orthopaedic surgery. Orthopedics 22(1 Suppl):s113–s118, 1999.
4. Desmond MJ, Thomas MJ, Gillon J, Fox MA: Consensus conference on autologous transfusion: Perioperative red cell salvage. Transfusion 36:644–651, 1996.
5. Faris PM, Ritter MA, Abels RI: The effects of recombinant human erythropoietin on perioperative transfusion requirements in patients having a major orthopaedic operation: The American Erythropoietin Study Group. J Bone Joint Surg 78A:62–72, 1996.
6. Goldberg MA: A safety and efficacy comparison study of two dosing regimens of epoetin alfa in patients undergoing major orthopedic surgery. Am J Orthop 25:544–552, 1996.
7. Gombotz H, Gries M, Sipurzynski S, Fruhwald S, Rehak P: Preoperative treatment with recombinant human erythropoietin or predeposit of autologous blood in women undergoing primary hip replacement. Acta Anaesthesiol Scand 44:737–742, 2000.
8. Grosvenor D, Goyal V, Goodman S: Efficacy of postoperative blood salvage following total hip arthroplasty in patients with and without deposited autologous units. J Bone Joint Surg 82A:951–954, 2000.
9. National Institutes of Health: Consensus conference: Perioperative red blood cell transfusion. JAMA 260:2700–2703, 1988.
10. Nelson CL, Bowen WS: Total hip arthroplasty in Jehovah’s Witnesses without blood transfusion. J Bone Joint Surg 68A:350–353, 1986.
11. Oishi CS, D’Lima DD, Morris BA, et al: Hemodilution with other reinfusion techniques in total hip arthroplasty. Clin Orthop 339:132–139, 1997.
12. Spence RK: Anemia in the patient undergoing surgery and the transfusion decision: A review. Clin Orthop 357:19–29, 1998.
13. Stowell CP, Chandler H, Jove M, Guilfoyle M, Wacholtz MC: An open-label, randomized study to compare the efficacy of perioperative EPO with preoperative autologous donation in total joint arthroplasty. Orthopedics 22(1 Suppl):s105–s112, 1999.
© 2004 Lippincott Williams & Wilkins, Inc.